Diphosphonic acids or salts thereof are used in therapy to inhibit bone reabsorption.
Monosodium ibandronate, for example, is used in particular for the treatment and prevention of osteoporosis, neoplasms-associated hypercalcemia, Paget's disease and related pathologies.
Monosodium ibandronate is currently available on the market in the anhydrous [RN=138844-81-2] and monohydrate [RN=138926-19-9] crystalline form.
The preparation of ibandronic acid and salts thereof is disclosed in U.S. Pat. No. 4,927,814 and DE 3623397.
One of the main problems related to the synthesis of diphosphonic acids is the solidification of the reaction mixture, which makes it difficult to carry out the reaction on an industrial scale and does not provide satisfactory yields (yields are generally of about 50%).
In particular, the production of risedronic, zoledronic and ibandronic acid requires starting materials that are costly and not easily available.
U.S. Pat. No. 4,927,814 discloses the preparation of 1-hydroxy-3-(N-methyl-N-pentylamino)propane-1,1-diphosphonic acid (ibandronic acid) by reaction of 3-(N-methyl-N-pentylamino)propionic acid with phosphorus trichloride and phosphorous acid in chlorobenzene. At the end of the reaction the solvent is removed by decantation and the resulting solid mass is first hydrolyzed with hydrochloric acid, then filtered, concentrated to a semifluid mass and purified through a resin (Amberlite IR 120). These operations are particularly difficult and dangerous when carried out on an industrial scale.
U.S. Pat. No. 5,583,122 discloses 1-hydroxy-2-(3-pyridyl)ethane-1,1-diphosphonic acid (risedronic acid), but its preparation is not exemplified. On the contrary, the patent discloses the synthesis of an isomer, 1-hydroxy-2-(2-pyridyl)ethane-1,1-diphosphonic acid, by reaction of (2-pyridyl)acetic acid with phosphorous acid and phosphorus trichloride in chlorobenzene. At the end of the reaction the mixture solidifies and the solvent must be removed by decantation. This operation is difficult to carry out on an industrial scale and the addition of water necessary to hydrolyse the solid mass is dangerous. Yield amounts to 52%.
EP 1243592 discloses the synthesis of risedronic acid following the same general procedure as U.S. Pat. No. 5,583,122, starting from (3-pyridyl)acetic acid hydrochloride. The product is isolated in a 50% yield, without adding solvents to promote precipitation.
U.S. Pat. No. 4,939,130 discloses the synthesis of 1-hydroxy-2-(1-imidazolyl)ethane-1,1-diphosphonic acid (zoledronic acid) by reaction of (1-imidazolyl)acetic acid hydrochloride with phosphorus trichloride and 85% phosphoric acid in chlorobenzene. Also in this case a semisolid mass separates from the reaction mixture and chlorobenzene must be decanted off.
J. Org. Chem. 1995, 60, 8310-8312, states that the use of phosphorus oxychloride and phosphorous acid causes solidification of the reaction mixture.
IT 1230503 discloses the preparation of 8-amino-1-hydroxyoctane-1,1-diphosphonic acid by reaction of 8-amino-octanoic acid with a mixture of phosphorous acid and phosphorus trichloride, with or without solvents. When no solvent is used, the optimal 8-amino-octanoic acid: phosphorous acid: phosphorus trichloride molar ratio is 1:3:1.5.